Most DNA viruses replicate in the nucleus, which provides the cellular factors required for the amplification and transcription of the viral genomes and for posttranscriptional processing of the viral mRNA. This suggests that after crossing the plasma membrane or endocytic membrane, released viruses or their components must also traverse the cytoplasm to enter the nucleus.
The cytoplasm imposes a diffusion barrier caused by high viscosity and steric obstacles. Cytoplasmic solutes and macromolecules, along with the lattice-like mesh of microtubules, actin, and intermediate filament networks, restrict the free diffusion of macromolecular complexes larger than 500 kDa, indicating that virus-sized particles are unlikely to move efficiently through the cytosol by diffusion alone. It is likely that viruses would need to be actively transported during their cytoplasmic trafficking. Microtubules are polarized structures with a fast-growing plus end extending toward the cell periphery and a slow-growing minus end located at the centrosome or microtubule organizing center (MTOC), which is typically found in a perinuclear position. Directed transport of cellular components is linked to large complexes that form molecular motors. Cytoplasmic dynein and kinesin are known to mediate organelle movement in opposite directions along microtubules. Cytoplasmic dynein, a minus-end-directed, microtubule-based motor, is a multisubunit protein complex of 1,270 kDa consisting of two heavy chains (530 kDa), two or three intermediate chains (74 kDa), and a variable number of small subunits. The ATPase and microtubule motor domains are located within the dynein heavy chains, whereas the specific cargo-binding activity involves the intermediate chains and several classes of light chains (Boylan et al., Mol. Biol. Cell, 11:3791-3803, 2000 and Vaughan et al., J. Biol. Chem., 276:26171-16179, 2001). In many cases the microtubule-dependent transport of material is facilitated by the dynein activator protein dynactin, which mediates dynein binding to microtubules (Allan, Curr. Biol., 6:630-633, 1996). Dynein, in conjunction with dynactin, facilitates membrane transport from the early endosomes to late endosomes and lysosomes and from the endoplasmic reticulum to the Golgi apparatus.
The involvement of microtubules in cytoplasmic traffic has been reported for a number of viruses, and dynein-mediated transport has been described for adenovirus (Leopold et al., Hum. Gene ther., 11:151-165, 2000; Suomalainen et al., J. Cell Biol., 144:657-672, 1999 and Suomalainen et al., EMBO J., 20:1310-1319, 2001), human foamy virus (Saib et al., Virology, 228:263-268, 1997), herpes simplex virus type 1 (HSV-1) (Dohner et al., Mol. Biol. Cell, 13:2795-2809, 2002; Sodeik et al., J. Cell Biol., 136:1007-1021, 1997 and Ye et al., J. Virol., 74:1355-1363, 2000), and African swine fever virus (ASFV) (Alonso et al., J. Virol., 75:9818-9827, 2001). In addition, vaccinia virus exploits microtubules to enhance its exit from infected cells. Vaccinia virus particles, using microtubule plus-end-directed kinesin as a motor, are transported along microtubules from the perinuclear site of assembly to the site of exit at the plasma membrane (Ploubidou et al., EMBO J., 19:3932-3944, 2000 and Rietdorf et al., Nat. Cell Biol., 3:992-1000, 2001). Poxviruses due to their large size (approximately 250-300 μm) are dependent on active transport through microtubules for intracellular movement during infection (Ward, Cell Microbiol., 7:1531-1538, 2005).
Influenza virus vaccines, and their components, have been used to treat other virus infections, such as herpes virus infections, as reported in Lieberman, Clinical Ecology, 7(3):51-54 (1990) and McMichael U.S. Pat. Nos. 4,521,405 and 4,880,626, all of which are incorporated herein by reference. Influenza vaccines induce a modified immune response such that symptoms were alleviated as a consequence of neutralizing the body's response to the infectious agent by stimulating suppressor T-cells. The T-cells in turn down-regulated effector cells and thus interrupted the allergic-type reaction induced by simultaneous lysis of many cells infected with the influenza virus. However, the results reported by McMichael and Lieberman attributed the anti-herpes virus effects of influenza virus vaccines to the presence of thimerosal, a preservative present in commercially available influenza virus vaccines, and not to a portion of the killed influenza virus, such as a surface antigen. Further, it has been discovered that the anti-herpes virus activity of influenza virus vaccines is attributable to the presence of thimerosal in the tested compositions and that herpes virus infections can be treated with thimerosal uncombined with or in the absence of influenza virus vaccine. Related to this is the disclosure of Manfuso, U.S. Pat. No. 4,803,991 which teaches the treatment of herpes virus infections by the topical administration of thimerosal, but does not teach or suggest the administration of thimerosal systemically.
In vitro assays with purified thimerosal demonstrate activity against herpes viruses (U.S. Pat. Nos. 4,803,991; 5,753,624; and 6,174,916). Of interest is the observation that when thimerosal is mixed in a test tube with herpes virus and is subsequently introduced into susceptible cells, viral propagation is not inhibited. This suggests that the anti-herpes viral activity of thimerosal is not by direct action on the virus. Further study shows that thiosalicylic acid and dithiodibenzoic acid, which are the breakdown products of thimerosal, do not provide antiviral activity in vivo although dithiodibenzoic acid indicated anti-herpes virus activity in vitro.
Adenoviruses most commonly cause respiratory illness; however, depending on the infecting serotype, they may also cause various other illnesses, such as gastroenteritis, conjunctivitis, cystitis, and rash illness. Symptoms of respiratory illness caused by adenovirus infection range from the common cold syndrome to pneumonia, croup, and bronchitis. Patients with compromised immune systems are especially susceptible to severe complications of adenovirus infection.
Although epidemiologic characteristics of the adenoviruses vary by type, all are transmitted by direct contact, fecal-oral transmission, and occasionally waterborne transmission. Some types are capable of establishing persistent asymptomatic infections in tonsils, adenoids, and intestines of infected hosts, and shedding can occur for months or years. Outbreaks of adenovirus-associated respiratory disease have been more common in the late winter, spring, and early summer; however, adenovirus infections can occur throughout the year.
Most infections with adenovirus result in infections of the upper respiratory tract. Adenovirus infections often show up as conjunctivitis, tonsillitis, an ear infection, or croup. Adenoviruses can also cause gastroenteritis (stomach flu). A combination of conjunctivitis and tonsillitis is particularly common with adenovirus infections. Some children (especially small ones) can develop adenovirus bronchiolitis or pneumonia, both of which can be severe. Other clinical syndromes associated with adenoviruses include, but are not limited to, pharyngitis, pharynconjunvtical fever, acute respiratory disease of recruits, pneumonia, follicular conjunctivitis, epidemic ketatoconjunctivitis, pertussis-like syndrome, acute hemorrhagic cystitis, acute infantile gastroenteritis, intussception and meningitis.
Papillomas are benign epithelial tumors that are caused by infection with the human papilloma virus (HPV). They are the most common benign neoplasms affecting the larynx and upper respiratory tract. Clinical manifestations associated with HPV include, but not are limited to, benign warts, juvenile laryngeal papillomatosis and epidermodysplasia verruciformis.
Pox viruses are generally enveloped and vary in shape depending upon the species but are generally shaped like a brick or as an oval form similar to a rounded brick because that are wrapped by the endoplasmic reticulum. The virion is exceptionally large (200 nm in diamete4 and 300 nm in length) and carries its genome in a single, linear double-stranded segment of DNA. In some embodiments, the pox virus is a varicella zoster virus. A varicella zoster viral infection is also known as the chicken pox. Chickenpox is often heralded by a prodrome of myalgia, nausea, fever, headache, sore throat, pain in both ears, complaints of pressure in head or swollen face, and malaise in adolescents and adults, while in children the first symptom is usually the development of a papular rash, followed by development of malaise, fever (a body temperature of 38° C. (100° F.), but may be as high as 42° C. (108° F.) in rare cases), and anorexia. Typically, the disease is more severe in adults. Chickenpox is rarely fatal, although it is generally more severe in adult males than in adult females or children. Pregnant women and those with a suppressed immune system are at highest risk of serious complications. The most common late complication of chickenpox is shingles, caused by reactivation of the varicella zoster virus decades after the initial episode of chickenpox.
Polyoma viruses are DNA-based, small (40-50 nm is diameter) and icosahedral in shape and do not have a lipoprotein envelope. JV virus can infect the respiratory system, kidneys or brain. BK virus produces a mild respiratory infection and can affect the kidneys of immunosuppressed transplant patients. Both of these polyoma viruses are widespread and are highly common in childhood and young adult infections.